CN107185034B - Bone-cartilage defect integrated repair biological ceramic scaffold and preparation method and application thereof - Google Patents

Bone-cartilage defect integrated repair biological ceramic scaffold and preparation method and application thereof Download PDF

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CN107185034B
CN107185034B CN201710308461.9A CN201710308461A CN107185034B CN 107185034 B CN107185034 B CN 107185034B CN 201710308461 A CN201710308461 A CN 201710308461A CN 107185034 B CN107185034 B CN 107185034B
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CN107185034A (en
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吴成铁
邓翠君
常江
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Shanghai Institute of Ceramics of CAS
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    • B28—WORKING CEMENT, CLAY, OR STONE
    • B28B—SHAPING CLAY OR OTHER CERAMIC COMPOSITIONS; SHAPING SLAG; SHAPING MIXTURES CONTAINING CEMENTITIOUS MATERIAL, e.g. PLASTER
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Abstract

The invention relates to a bone-cartilage defect integrated repair biological ceramic bracket, a preparation method and application thereof, wherein the biological ceramic bracket comprises: the three-dimensional tricalcium phosphate ceramic support comprises a three-dimensional tricalcium phosphate ceramic support and manganese ions uniformly distributed in the three-dimensional tricalcium phosphate ceramic support. The biological ceramic bracket of the invention realizes the bidirectional biological function of cartilage-subchondral bone integrated repair of the articular osteochondral complex defect.

Description

Bone-cartilage defect integrated repair biological ceramic scaffold and preparation method and application thereof
Technical Field
The invention relates to a novel bifunctional biological ceramic bracket and a preparation method and application thereof, belonging to the field of biological materials.
Background
Complex tissue of bone-cartilage also called osteochondral complex, including articular cartilage and subchondral bone[1]Cartilage and subchondral bone are integral and are interdependent and inseparable[2]. Many factors causing articular cartilage defect, such as trauma, disease, congenital malformation, aging and improper exercise, etc., and the articular cartilage self-repairing ability is very poor due to the physiological characteristics of cartilage tissue, so that joint dysfunction and subchondral bone involvement are frequently caused by cartilage injury[3-7]. In repairing cartilage defectAt the same time of damage, the relationship between subchondral bone and articular cartilage must be highly regarded, and the aim is to repair the osteochondral complex at the same time and integrally. In surgical operations, the methods for repairing osteochondral complexes generally employ bone marrow stimulation and artificial material implantation, and although the bone marrow stimulation is simple in operation, relatively satisfactory in the treatment of small-area injuries and widely used in clinical practice, the mechanical properties and elastic modulus of fibrocartilage tissues formed by healing cartilage erosion, bone marrow stimulation and the like are inferior to those of natural osteochondral complexes and are easily degraded[8]. At present, the artificial material implant material can be divided into high molecular polymer, metal and biological ceramic according to the main components, the mechanical strength of the high molecular polymer can not meet the requirements of osteochondral complex, and the biocompatibility of the high molecular polymer is poor; metals such as titanium and titanium alloy can satisfy the mechanical strength requirement of osteochondral complex, and have good biocompatibility, and the released trace metal ions can promote repair[9,10]But the degradation performance is poor, and the long-term existence of the composition in vivo can cause inflammation to cause the failure of the operation. Therefore, how to develop a bioceramic scaffold material with the dual-function characteristic of cartilage-subchondral bone integrated repair is still very challenging.
Earlier studies have shown that tricalcium phosphate has good in vitro and in vivo biological activity, mainly expressed in one or some of the following aspects: can induce the formation of bone-like apatite in the environment of body fluid; the function of inducing or promoting osteogenic differentiation of various stem cells is realized; has good degradability and osteogenic and vascularization capacity in vivo[11-13]. However, tricalcium phosphate does not have a cartilage repair function and cannot be used for repairing articular cartilage defects.
Prior art documents:
[1]Kazunori S.,Yu M.,Christopher D.M.,et al.Osteochondral tissueengineering with biphasic scaffold:current strategies and techniques[J].Tissue Engineering:Part B,2014；20(5):468-476.
[2]Madry H.,van Dijk C.,Mueller-Gerbl M,et al.The basic science ofthe subchondral bone[J].Knee Surg Sports Traumatol Arthrosc,2010；18(4):419-433.
[3]Mark B.H.,Michael D.B.,Lisa A.F.,et al.Preclinical Studies forCartilage Repair:Recommendations from the International Cartilage RepairSociety[J].Cartilage,2011；2(2):137-152.
[4]Rudert M.Histological evaluation of osteochondral defects:consideration of animal models with emphasis on the rabbit,experimentalsetup,follow-up and applied methods[J].Cells Tissues Organs,2002；171(4):229-240.
[5]Frosch K.H.,Drengk A.,Krause P.,et al.Stem cell-coated titaniumimplants for the partial joint resurfacing of the knee[J].Biomaterials,2006；27(12):2542-2549.
[6]Shao X.X.,Hutmacher D.W.,Ho S.T.,et al.Evaluation of a hybridscaffold/cell construct in repair of high-load-bearing osteochondral defectsin rabbits[J].Biomaterials,2006；27(7):1071-1080.
[7]Ghosh S.,Viana J.C.,Reis R.L.,et al.Bi-layered constructs based onpoly(L-lactic acid)and starch for tissue engineering of osteochondral defects[J].Mater Sci Eng C,2008；28(1):80-86.
[8]Williams RJ 3rd,Harnly H.W.Microfracture:indications,technique,andresults[J].Instr Course Lect,2007；56:419-428.
[9]Yuanxun Z.,Feng C.,Deyi L.,et al.Investigation of ElementalContent Distribution in Femoral Head Slice with Osteoporosis by SRXRFMicroprobe[J].Biological Trace Element Research,2005；103:177-185.
[10]Bal B.S.,Rahaman M.N.,Jayabalan,P.,et al.In vivo outcomes oftissue-engineered osteochondral grafts[J].Biomed Mater Res B Appl Biomater,2010；93:164-172.
[11]Moore W.R.,Graves S.E.,Bain G.I.Synthetic bone graft substitutes[J].ANZ J Surg.2001；71:354-61.
[12]Mertz W..The essential trace elements[J].Science.1981；213:1332-8.
[13]Carlisle E.M..Silicon:an essential element for the chick[J].Science.1972；178:619-21.。
disclosure of Invention
Aiming at the problems in the prior art, the invention aims to provide a biological ceramic scaffold with a cartilage-subchondral bone defect repairing function, and a preparation method and application thereof.
One aspect of the present application provides a bioceramic scaffold, comprising: a three-dimensional tricalcium phosphate ceramic scaffold, and manganese ions, such as divalent manganese ions, uniformly distributed in the three-dimensional tricalcium phosphate ceramic scaffold.
According to the invention, manganese ions are introduced into a three-dimensional tricalcium phosphate bioceramic scaffold, wherein the manganese ions can induce the low oxygen pressure (Hypoxia) of cells, activate the HIF-1 α signal path in chondrocytes, promote the proliferation and differentiation of chondrocytes, induce the autophagy mechanism of arthritic chondrocytes, and protect the chondrocytes, so that the bioceramic scaffold realizes the bidirectional biological function of cartilage-subchondral bone integrated repair of arthritic osteochondral complex defects.
Preferably, the bioceramic scaffold is obtained by three-dimensional printing. Therefore, the surface of the biological ceramic scaffold is compact, the pores are orderly and controllable, and the porosity of the biological ceramic scaffold can be 40-75%. Preferably, the content of manganese ions in the bioceramic scaffold is controllable, for example, the molar ratio of the manganese ions to the calcium ions can be (0.01-0.1): and (3) adjusting for 1 time.
The biological ceramic scaffold has excellent mechanical strength, and the compressive strength of the biological ceramic scaffold can be 6-16 MPa.
The application also provides a preparation method of the biological ceramic scaffold, which comprises the following steps:
(1) synthesizing tricalcium phosphate ceramic powder containing manganese ions by a coprecipitation method; and
(2) the biological ceramic bracket is prepared by taking tricalcium phosphate ceramic powder containing manganese ions as a raw material and adopting a three-dimensional printing technology.
According to the invention, the Mn-TCP biological ceramic scaffold is prepared by a method combining coprecipitation and three-dimensional printing technologies, and the method has the advantages of wide material source, simple process, easily-controlled conditions, low cost and the like. According to the invention, the structure of the obtained product can be accurately controlled through three-dimensional printing, so that the product is attractive, the pore ordered structure is controllable, and the mechanical strength of the product can be improved by regulating and controlling the porosity of the product.
Preferably, the tricalcium phosphate ceramic powder containing manganese ions is prepared by the following method:
adding alkali into a mixed solution containing a calcium source, a phosphorus source and a manganese source to adjust the pH value to 7.4-7.7, fully stirring for 12-36 hours, separating out solids, washing and drying to obtain precursor powder;
sintering the precursor powder at 600-900 ℃ for 3-5 hours to prepare the tricalcium phosphate ceramic powder containing manganese ions.
Preferably, the calcium source is a soluble calcium salt, preferably calcium nitrate;
the phosphorus source is soluble phosphate, preferably diammonium hydrogen phosphate;
the manganese source is soluble manganese salt, preferably at least one of manganese chloride and/or hydrate thereof, manganese nitrate and/or hydrate thereof.
Preferably, the mixed solution containing the calcium source, the phosphorus source and the manganese source is prepared by the following method:
preparing a manganese source and calcium source mixed solution, wherein the pH is 4.0-5.0, the concentration of Mn ions in the solution is 0.01-0.06 mol/L, and the concentration of Ca ions in the solution is 0.5-0.6 mol/L;
preparing a phosphorus source solution, wherein the pH is 7.5-8.5, and the concentration of the phosphorus source is 0.4-0.6 mol/L;
and dropwise adding the mixed solution of the manganese source and the calcium source into the phosphorus source solution.
Preferably, step (2) includes:
preparing tricalcium phosphate ceramic powder containing manganese ions: sodium alginate: the mass ratio of the poloxamer (F127) aqueous solution is 1: (0.05-0.15): (0.6-1.2) mixing to obtain a paste;
placing the obtained paste into a three-dimensional printer for three-dimensional printing to obtain a blank body;
and sintering the obtained blank at 1000-1200 ℃ for 2-6 hours to obtain the biological ceramic bracket.
Preferably, the particle size of the tricalcium phosphate ceramic powder containing manganese ions is less than or equal to 75 microns, the particle size of the sodium alginate is less than or equal to 50 microns, and the concentration range of the F127 is 10-20%.
The application also provides application of the biological ceramic scaffold in preparation of the cartilage-subchondral bone defect integrated repair implant material.
The biological ceramic scaffold can be used as a cartilage-subchondral bone defect implantation material, has excellent in-vitro biological activity, and has remarkable two-way biological functional characteristics of in-vivo cartilage-subchondral bone integrated repair. Therefore, the biological ceramic scaffold has wide application prospect in the field of cartilage-subchondral bone defect repair.
Drawings
FIG. 1 is a diagram showing the physical and chemical properties of Mn-TCP bioceramic powder, (A) XRD (X-ray diffraction pattern) of Mn-TCP bioceramic at 650 ℃, (B) micropellet thermogravimetric curve of Mn-TCP bioceramic, (C) unit cell parameters of Mn-TCP bioceramic, and (D) unit cell volume of Mn-TCP bioceramic. The physical and chemical property characterization chart shows that the crystal phase transition temperature of the Mn-TCP bioceramic is reduced along with the increase of Mn content, and the unit cell parameters and the unit cell volume are reduced along with the increase of Mn content;
FIG. 2 is a representation diagram of the morphology of a Mn-TCP bioceramic stent, (A-C) TCP, (D-F)2.5 Mn-TCP, (G-I) 5Mn-TCP, (J-L) 10 Mn-TCP. the graph shows that as the Mn content increases, the color of the stent gradually changes from light pink to dark pink, and the surface morphology of the stent also changes from the porous structure of TCP to dense liquefied morphology;
FIG. 3 is a representation diagram of a Mn-TCP bioceramic stent, (A) manganese content of the stent, (B)2.5 Mn-TCP stent X-ray photoelectron spectroscopy, (C) 5Mn-TCP stent X-ray photoelectron spectroscopy, (D)10 Mn-TCP stent X-ray photoelectron spectroscopy, (E) a partially enlarged view of a graph B, (F) a partially enlarged view of a graph C, and (G) a partially enlarged view of a graph D. Research results show that the actual manganese content of the bracket increases along with the increase of doping amount, the range of the actual manganese content is 2.284-8.588% (mole percentage content), and the valence state of the manganese is positive bivalence as proved by X-ray photoelectron spectroscopy analysis;
FIG. 4 is a diagram showing the physical and chemical properties of a Mn-TCP bioceramic scaffold, (A) the Mn-TCP bioceramic scaffold used for mechanical property tests, (B) the compressive strength of the Mn-TCP bioceramic scaffold, (C) the degradation performance of the Mn-TCP bioceramic scaffold, and (D) the Mn ion release of the Mn-TCP bioceramic scaffold. The graph shows that the compressive strength of the Mn-TCP biological ceramic scaffold is obviously improved along with the increase of Mn content, and the degradability of the scaffold and the release energy of Mn ions are improved along with the increase of Mn content;
FIG. 5 is a gene expression diagram of bone marrow mesenchymal stem cells (rBMSC) and chondrocytes, (A-D) expressions of cartilage specific genes CO L II, Aggrecan, SOX9 and N-cadh genes, (E-H) expressions of osteogenic differentiation key genes CO L I, BMP2, OPN and RUNX2, wherein in each column, four columns from left to right are sequentially TCP, 2.5Mn-TCP, 5Mn-TCP and 10Mn-TCP, and the Mn-TCP bioceramic leaching solution remarkably promotes the expressions of the cartilage specific genes and the osteogenic differentiation key genes;
FIG. 6 is a representation of the activity and mineralization of alkaline phosphatase (A L P), (A) quantification of A L P, (B) staining of A L P, (C) quantification of alizarin red, and (D) staining of alizarin red, wherein the Mn-TCP bioceramic leach solution significantly improves the activity of A L P of mesenchymal stem cells and effectively promotes the formation of calcium nodules;
FIG. 7 proliferation and adhesion of chondrocytes and mesenchymal stem cells on Mn-TCP bioceramic scaffolds. (A) Proliferating chondrocytes on a bracket, (B) adhering the chondrocytes on the bracket, (C) proliferating mesenchymal stem cells on the bracket, and (D) adhering the mesenchymal stem cells on the bracket. The figure shows that the Mn-TCP biological ceramic scaffold remarkably promotes the proliferation and adhesion of chondrocytes and bone marrow mesenchymal stem cells;
fig. 8 shows that Mn ions promote osteogenic differentiation of mesenchymal stem cells and differentiation of chondrocytes, (a) staining of a L P, (B) staining of alizarin red, (C) quantification of a L P activity, and (D) quantification of alizarin red, and that Mn ions significantly improve a L P activity and promote mineralization within a certain concentration range;
FIG. 9 mechanism of Mn ion promotion of chondroproliferative differentiation and autophagy, (A) expression of HIF-1 α gene, (B) expression of MMP3 gene, (C) expression of MMP13 gene, (D) expression of Adamts gene it is shown that Mn ion promotes chondrocytic differentiation by activating HIF-1 α, while Mn ion protects it from degradation by activating chondrocytic autophagy;
FIG. 10 in vivo repair Effect of Mn-TCP bioceramic scaffold, A1-D4Material implantation for 8 weeks (A)1-4) Blank control group, (B)1-4) TCP group, (C)1-4)5Mn-TCP group, (D)1-4)10Mn-TCP group; e1-H4Material implantation for 12 weeks, (E)1-4) Blank control group, (F)1-4) TCP group, (G)1-4)5Mn-TCP group, (H)1-4)10Mn-TCP group. It is shown that the Mn-TCP bioceramic scaffold group significantly promoted cartilage-subchondral bone repair compared to the placebo and TCP groups;
FIG. 11 histochemical compositional analysis, A1-H3Safranin O staining, (A)1-A3,E1-E3) Blank control group, (B)1-B3,F1-F3) TCP group, (C)1-C3,G1-G3)5Mn-TCP group, (D)1-D3,H1-H3)10Mn-TCP group, I-P alizarin Red staining, (I, M) blank control group, (J, N) TCP group, (K, O)5Mn-TCP group, (L, P)10Mn-TCP group, it is shown that the blank control group and the 10Mn-TCP group are present 8 weeks after the material was implantedA small amount of a mixture of new bones and fibrous tissues is formed around the bone defect of the pure TCP group, and a certain amount of new cartilage and subchondral bone is formed around the bone defect and in the center of the Mn-TCP bioceramic scaffold group. After 12 weeks of implantation, the newly born cartilage and subchondral bone of the Mn-TCP bioceramic scaffold group completely covered the defect and had the formation of the tide line, while the blank control group and the pure TCP group had defects and the product contained a certain amount of fibrous tissues. The results show that the Mn-TCP bioceramic scaffold has excellent in-vivo cartilage-subchondral bone integrated repair performance.
Detailed Description
The present invention is further described below in conjunction with the following embodiments and the accompanying drawings, it being understood that the drawings and the following embodiments are illustrative of the invention only and are not limiting.
One embodiment of the invention provides a three-dimensional tricalcium phosphate biological ceramic scaffold (Mn-TCP biological ceramic scaffold or Mn-TCP scaffold for short) containing manganese ions, wherein the manganese ions are uniformly distributed in the three-dimensional tricalcium phosphate biological ceramic scaffold.
The chemical composition of the three-dimensional tricalcium phosphate biological ceramic scaffold is Ca3(PO4)2. The manganese ion can be Mn2+. In the Mn-TCP bioceramic scaffold, the molar ratio of manganese ions to calcium ions may be (0.01-0.1): 1, preferably (0.025 to 0.1): 1. the manganese ion content in the range can obviously promote the proliferation and differentiation of chondrocytes and bone marrow mesenchymal stem cells, and further promote the reconstruction of bone-cartilage defects. The Mn-TCP biological ceramic stent has a regular structure, the surface appearance is gradually liquefied along with the increase of the manganese content, the surface of the stent is densified, and the compressive strength of the Mn-TCP stent is improved and is 6-16 MPa. The color of the Mn-TCP bioceramic scaffold changes with the change of manganese content, the cell parameters and the crystal phase transition temperature are inversely proportional to the manganese content, for example, the a-axis length of the cell can be 10.370-10.440, the c-axis length can be 37.220-37.40, the cell volume can be 3470.10-3530.10, and the crystal phase transition temperature can be 600-900 ℃.
In one embodiment of the invention, the Mn-TCP biological ceramic scaffold is prepared by a method combining coprecipitation and three-dimensional printing technology. Specifically, tricalcium phosphate biological ceramic powder containing manganese ions is synthesized by a coprecipitation method, and a Mn-TCP biological ceramic bracket containing manganese ions and having double functions is prepared by utilizing a three-dimensional printing technology. The prepared Mn-TCP biological ceramic scaffold has excellent properties of osteogenesis, chondrogenesis and cartilage protection.
Concretely explaining the preparation of the tricalcium phosphate biological ceramic powder containing manganese ions. First, a mixed solution containing a calcium source, a phosphorus source, and a manganese source is prepared.
The calcium source is a soluble calcium salt, preferably calcium nitrate.
The source of phosphorus is a soluble phosphate salt, preferably diammonium phosphate.
The manganese source is a soluble manganese salt, preferably manganese chloride and/or a hydrate thereof (e.g. manganese chloride tetrahydrate).
In one example, a mixed aqueous solution of a calcium source and a manganese source is slowly dripped into a phosphorus source aqueous solution to obtain a mixed solution of the calcium source and the manganese source, the molar mass ratio of the manganese source to the calcium source is (1-10): 100, the content of manganese ions in the Mn-TCP bioceramic scaffold can be adjusted by adjusting the ratio of the manganese source to the manganese source, the pH of the mixed solution of the calcium source and the manganese source can be 4.0-5.0, the concentration of Mn ions in the solution can be 0.01-0.06 mol/L, the concentration of Ca ions in the solution can be 0.5-0.6 mol/L, the pH of the phosphorus source aqueous solution can be 7.5-8.5, the concentration can be 0.4-0.6 mol/L, and the molar ratio of the calcium source to the phosphorus source can be (0.5-1): 1.
And adding alkali into the mixed solution containing the calcium source, the phosphorus source and the manganese source to adjust the pH value to 7.4-7.7. The host substance generated in this pH range is tricalcium phosphate, and if the pH is greater than 8, hydroxyapatite is generated. The base may be aqueous ammonia (e.g., 10% aqueous ammonia). After the alkali is added, the mixture can be fully stirred at room temperature for 12 to 36 hours. And then separating out solids, washing and drying (for example, drying at 100-120 ℃ for 12-24 hours) to obtain precursor powder.
Calcining the precursor powder at a certain temperature to prepare Mn-TCP ceramic powder containing manganese ions. The calcination temperature may be 600 to 900 ℃ (preferably 650 to 850 ℃). The calcination time may be 3 to 5 hours.
And (3) taking the Mn-TCP ceramic powder as a three-dimensional printing raw material, and three-dimensionally printing the Mn-TCP biological ceramic support blank. When three-dimensional printing is carried out, the Mn-TCP ceramic powder can be mixed with sodium alginate and F127 (poloxamer) to obtain paste. Wherein, the sodium alginate can increase the viscosity and the elasticity of the sizing agent. F127 was used as a binder and dispersant. Mn-TCP ceramic powder: sodium alginate: the mass ratio of the F127 aqueous solution can be 1: (0.05-0.15): (0.6-1.2). The Mn-TCP ceramic powder particle size can be less than or equal to 75 μm. The powder with the granularity can easily pass through the printing needle head, so that the needle head is not easy to block. The particle size of the sodium alginate powder can be less than or equal to 50 μm. The sodium alginate with the granularity range is easy to be uniformly mixed with the ceramic powder, so that the slurry is better in uniformity. The concentration of the F127 aqueous solution can be 10-20% by mass fraction. And during three-dimensional printing, the specific parameters of the support are designed by using a program, and the shape, the size and the like of the support are regulated and controlled. And sintering the printed blank to obtain the Mn-TCP biological ceramic bracket. The sintering temperature can be 1000-1200 ℃. The sintering time can be 2-6 hours.
The phase, manganese content, thermal property, surface morphology, porosity and the like of the Mn-TCP bioceramic can be systematically characterized by means of XRD, XRF, TG-DTA, an optical microscope, SEM, Micro-CT and the like.
Bidirectional biological performance research of Mn-TCP biological ceramic
In vitro osteogenesis induction promoting property of Mn-TCP bioceramic
Culturing bone marrow mesenchymal stem cells of rabbits by using different Mn-TCP bioceramic scaffolds or leaching solutions thereof, researching adhesion and proliferation of materials to the bone marrow mesenchymal stem cells and expression of genes and proteins related to osteogenesis, carrying out quantitative and qualitative analysis on early osteogenesis performance by using an alkaline phosphatase kit, and evaluating mineralization at the final stage of osteogenesis by using an alizarin red staining method. Research results show that the Mn-TCP biological ceramic scaffold and the ion product released by the Mn-TCP biological ceramic scaffold remarkably promote the adhesion, proliferation and osteogenic differentiation of bone marrow mesenchymal stem cells, and prove that the material has osteogenic promotion.
Promotion of ectochondrogenic differentiation of Mn-TCP bioceramic bodies
The research results show that the Mn-TCP bioceramic scaffold and the ion products released by the Mn-TCP bioceramic scaffold remarkably promote the adhesion and proliferation of chondrocytes and the expression of specific genes and proteins of the chondrocytes, and the Mn ions have the effects of activating an HIF-1 α signal channel and autophagy of the chondrocytes, thereby proving that the material has the biological activities of forming cartilage and protecting the chondrocytes.
Effect of Mn-TCP (manganese-transmission control protocol) biological ceramic scaffold on cartilage-subchondral bone integrated repair
The invention proves that the Mn-TCP bioceramic has the cartilage-subchondral bone integrated repair effect for the first time. Micro-CT results show that the newly grown cartilage and subchondral bone formed at the defect position by implanting the Mn-TCP biological ceramic scaffold are remarkably increased compared with a blank group control and a pure TCP group. Histochemical staining analysis showed that after 8 weeks of implantation of the material, a small amount of a mixture of new bone and fibrous tissue was formed around the bone defect in the blank control group and the pure TCP group, whereas the Mn-TCP bioceramic scaffold group had a certain amount of new cartilage and subchondral bone formation around the bone defect and in the center of the scaffold. After 12 weeks of implantation, the newly born cartilage and subchondral bone of the Mn-TCP bioceramic scaffold group completely covered the defect and had the formation of the tide line, while the blank control group and the pure TCP group had defects and the product contained a certain amount of fibrous tissues. The results show that the Mn-TCP bioceramic scaffold has excellent in-vivo cartilage-subchondral bone integrated repair performance.
The present invention will be described in detail by way of examples. It is also to be understood that the following examples are illustrative of the present invention and are not to be construed as limiting the scope of the invention, and that certain insubstantial modifications and adaptations of the invention by those skilled in the art may be made in light of the above teachings. The specific process parameters and the like of the following examples are also only one example of suitable ranges, i.e., those skilled in the art can select the appropriate ranges through the description herein, and are not limited to the specific values exemplified below.
Example 1:
dissolving diammonium phosphate in deionized water (the pH value is 8, the concentration is 0.5 mol/L), respectively mixing and dissolving manganese chloride tetrahydrate and calcium nitrate in the deionized water according to the molar mass of (2.5, 5, 10): 100, dropwise adding the obtained mixed solution of the manganese chloride tetrahydrate and the calcium nitrate (the pH value is 4.5, the Mn ion concentration is 0.012 mol/L, 0.024 mol/L, 0.05 mol/L and the Ca ion concentration is 0.5 mol/L) into the diammonium phosphate solution, adjusting the pH value to 7.49-7.53 by using 10% ammonia water, fully stirring for 24 hours at room temperature, carrying out suction filtration, washing for three times by using the deionized water, washing for three times by using absolute ethyl alcohol, drying for 12 hours at the temperature of 100 ℃, and sintering for 3 hours at the temperature of 800 ℃ to prepare Mn-TCP (manganese-transmission control protocol) bioceramic powder with different Mn contents;
the obtained series of Mn-TCP ceramic powders (the granularity is 50 μm): sodium alginate (particle size 50 μm): f127 (concentration of 20%) was added in a mass ratio of 1: 0.12: 1.2, mixing, designing a printing program by using software, carrying out three-dimensional printing, and sintering the obtained scaffold at 1100 ℃ for 3 hours to obtain the Mn-TCP biological ceramic scaffold.
The obtained Mn-TCP bioceramic scaffold is respectively marked as 2.5Mn-TCP, 5Mn-TCP and 10 Mn-TCP. The obtained Mn-TCP bioceramic scaffold is subjected to material characterization, and researches on osteogenesis, chondrogenesis performance and in-vivo repair effect are carried out. The results are shown in FIGS. 1-11, and the porosity of the alloy decreases with the increase of the manganese content by Micro-CT, and is respectively 68.5%, 58.3% and 45.8%.
Example 2:
dissolving diammonium phosphate in deionized water (the pH value is 7.5, the concentration is 0.4 mol/L), mixing and dissolving manganese chloride tetrahydrate and calcium nitrate in the deionized water according to the molar mass of 4: 100, dropwise adding the obtained mixed solution of the manganese chloride tetrahydrate and the calcium nitrate (the pH value is 4, the Mn ion concentrations are 0.02 mol/L and the Ca ion concentration is 0.4 mol/L) into a diammonium phosphate solution, adjusting the pH value to be 7.53-7.62 by using 10% ammonia water, fully stirring for 24 hours at room temperature, performing suction filtration, washing for three times by using the deionized water, washing for three times by using absolute ethyl alcohol, drying for 12 hours at the temperature of 100 ℃, and sintering for 4 hours at the temperature of 700 ℃ to obtain Mn-TCP biological ceramic powder;
the obtained Mn-TCP ceramic powder (particle size 75 μm): sodium alginate (particle size 20 μm): f127 (concentration of 10%) is mixed by mass ratio of 1: 0.05: 0.6, and designing a printing program by using software, carrying out three-dimensional printing, and sintering the obtained scaffold at 1000 ℃ for 2 hours to obtain the Mn-TCP biological ceramic scaffold.
The Mn-TCP bioceramic scaffold can well induce the adhesion and proliferation of bone marrow mesenchymal stem cells and cartilage cells of rabbits, the leaching liquor of the Mn-TCP bioceramic scaffold can obviously improve the transcription of bone marrow stromal stem cell osteogenesis related genes and the expression of proteins, and effectively improve the formation of an osteogenic early marker alkaline phosphatase and a bone end-stage mineralized substance, namely a calcium nodule, and meanwhile, the leaching liquor of the Mn-TCP bioceramic scaffold also can obviously increase the expression of chondrocyte specific genes and proteins, Mn ions released by the Mn-TCP bioceramic scaffold can obviously promote the expression of a hypoxic-pressure factor (HIF-1 α) of chondrocytes, and can also induce the autophagy of chondrocytes in arthritis to protect the chondrocytes.
Example 3:
dissolving diammonium phosphate in deionized water (the pH value is 8.5, the concentration is 0.6 mol/L), mixing and dissolving manganese chloride tetrahydrate and calcium nitrate in the deionized water according to the molar mass of 7.5: 100, dropwise adding the obtained mixed solution of the manganese chloride tetrahydrate and the calcium nitrate (the pH value is 5, the concentrations of Mn ions are 0.0375 mol/L and Ca ions are 0.6 mol/L), adjusting the pH value to 7.6-7.7 by using 10% ammonia water, fully stirring for 24 hours at room temperature, performing suction filtration, washing for three times by using the deionized water, washing for three times by using absolute ethyl alcohol, drying for 12 hours at the temperature of 100 ℃, and sintering for 5 hours at the temperature of 900 ℃ to obtain Mn-TCP biological ceramic powder;
the obtained Mn-TCP ceramic powder (particle size 75 μm): sodium alginate (particle size 50 μm): f127 (concentration of 15%) was added in a mass ratio of 1: 0.15: 1.0, mixing, designing a printing program by using software, carrying out three-dimensional printing, and sintering the obtained support at 1200 ℃ for 6 hours to obtain the Mn-TCP biological ceramic support.
The obtained Mn-TCP bioceramic scaffold is characterized, and the study on the properties of osteogenesis and cartilage formation and the in-vivo repair effect is carried out. The result also shows that the Mn-TCP bioceramic scaffold obtained in the embodiment has excellent bioactivity in vitro, has the performance of cartilage-subchondral bone integrated repair in an animal body, and is a potential bifunctional hard tissue bioactive implant material.

Claims (11)

1. A biological ceramic bracket is characterized in that a biological ceramic bracket with a bidirectional biological function for integrally repairing cartilage-subchondral bone is prepared by taking tricalcium phosphate biological ceramic powder containing manganese ions synthesized by a coprecipitation method as a raw material and utilizing a three-dimensional printing technology; the biological ceramic scaffold comprises a three-dimensional tricalcium phosphate ceramic scaffold and manganese ions uniformly distributed in the three-dimensional tricalcium phosphate ceramic scaffold; wherein the molar ratio of manganese ions to calcium ions is (0.01-0.1): 1.
2. the bioceramic scaffold according to claim 1, wherein the molar ratio of manganese ions to calcium ions is (0.025-0.1): 1.
3. the bioceramic scaffold according to claim 1, wherein the bioceramic scaffold has a compressive strength of 6-16 MPa.
4. A method for preparing a bioceramic scaffold according to any one of claims 1 to 3, comprising the steps of:
(1) synthesizing tricalcium phosphate ceramic powder containing manganese ions by a coprecipitation method; and
(2) the biological ceramic bracket is prepared by taking tricalcium phosphate ceramic powder containing manganese ions as a raw material and adopting a three-dimensional printing technology.
5. The production method according to claim 4,
the tricalcium phosphate ceramic powder containing manganese ions is prepared by the following method:
adding alkali into a mixed solution containing a calcium source, a phosphorus source and a manganese source to adjust the pH value to 7.4-7.7, fully stirring for 12-36 hours, separating out solids, washing and drying to obtain precursor powder;
sintering the precursor powder at 600-900 ℃ for 3-5 hours to prepare the tricalcium phosphate ceramic powder containing manganese ions.
6. The production method according to claim 5,
the calcium source is a soluble calcium salt;
the phosphorus source is soluble phosphate;
the manganese source is soluble manganese salt.
7. The method of claim 6, wherein the calcium source is calcium nitrate;
the phosphorus source is diammonium hydrogen phosphate;
the manganese source is at least one of manganese chloride and/or hydrate thereof, manganese nitrate and/or hydrate thereof.
8. The production method according to claim 5, wherein the mixed solution containing the calcium source, the phosphorus source, and the manganese source is produced by:
preparing a manganese source and calcium source mixed solution, wherein the molar mass ratio (1-10) of the manganese source to the calcium source is 100, the pH value is 4.0-5.0, the concentration of Mn ions in the solution is 0.01-0.06 mol/L, and the concentration of Ca ions in the solution is 0.5-0.6 mol/L;
preparing a phosphorus source solution, wherein the pH is 7.5-8.5, and the concentration of the phosphorus source is 0.4-0.6 mol/L;
and dropwise adding the mixed solution of the manganese source and the calcium source into the phosphorus source solution.
9. The method according to claim 4, wherein the step (2) comprises:
preparing tricalcium phosphate ceramic powder containing manganese ions: sodium alginate: the poloxamer F127 aqueous solution is prepared from the following components in a mass ratio of 1: (0.05-0.15): (0.6-1.2) mixing to obtain a paste;
placing the obtained paste into a three-dimensional printer for three-dimensional printing to obtain a blank body;
and sintering the obtained blank at 1000-1200 ℃ for 2-6 hours to obtain the biological ceramic bracket.
10. The preparation method of claim 9, wherein the particle size of the tricalcium phosphate ceramic powder containing manganese ions is less than or equal to 75 μm, the particle size of the sodium alginate is less than or equal to 50 μm, and the concentration range of the poloxamer F127 aqueous solution is 10% -20%.
11. Use of the bioceramic scaffold according to any one of claims 1 to 3 in the preparation of an integrated cartilage-subchondral bone defect repair implant material.
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